Growing evidence indicates that extracellular microRNAs stably exist in human body fluids, including plasma, saliva, urine, and milk. Accumulating data show the presence of RNase-resistant lipid vesicles, including exosomes and apoptotic bodies. However, very little is known about the secretory machinery of microRNAs and no data have shown conclusively that microRNAs act in a cell-to-cell manner, evoking a biological outcome in a living organism. The significance of our proposal is that we aim to evaluate the functional activity of exRNA in mouse models. We describe the development of a robust and quantitative positive readout for microRNA activity. Our plan is to use this 'pOSI-miR' technology in the most biologically relevant format- in the laboratory mouse. We combine this platform with a battery of existing exRNA microrRNA genetic knockout mouse models, teaming up with established exRNA experts to address biodistribution, uptake, and function in target cells in primary tissues comprising all known cell types. Our plan includes studies in cell culture, using the above systems to evaluate exRNA activity in ES cells and in neurons. In addition we further explore exRNA genetics using RNAi screening approaches in sensor cell lines. Finally we explore the uptake of exRNAs in a posi-sensor mouse model, laying a foundation for the development of exRNA therapeutics.